It is widely accepted that human cognition is supported by distributed neural networks engaged in a task dependent manner. Prefrontal cortex (PFC) is crucial to top-down control of such networks across multiple cognitive domains including attention, language and memory. Despite the widespread use of the term topdown control there is surprisingly little neurocognitive research on how or where this might be instantiated at a neural level. For instance, it is unknown whether excitation vs inhibition of activity in cognitive tasks represents a unitary gain control mechanism, such that activity is either up or down regulated along one continuum by one control mechanism or whether top-down control reflects the net activity of multiple and distinct RFC-dependent excitatory and inhibitory mechanisms. We propose that PFC exerts independent excitatory and inhibitory control to support goal-directed behavior. To address this hypothesis we will perform a series of experiments examining whether top-down is supported by distinct excitatory and inhibitory mechanisms with independent time courses. We will further assess whether top-down control is supported by excitement or inhibition of all of a certain class of stimuli based on pre-set instructions (Task Set top-down control) or whether PFC top-down control can also rapidly exert excitation and inhibition in early perceptual regions on a trial by trial basis (Trial-by-Trial top-down control). To address these questions we will perform fMRI studies in normal controls, electrocorticography studies (ECoG) in patients with implanted subdural electrodes and lesion studies in patients with focal PFC damage centered in mid-lateral PFC (BA 44/9/46). The ECoG studies will focus on the newly described high gamma response (70-250 Hz) that we have shown to be a robust neural marker of cortical activation. The patient lesion studies will be coupled with parallel TMS inactivation studies of mid-lateral PFC in normals. The lesion and TMS studies will assess whether the proposed lateral PFC activations observed in the ECoG and TMS studies are critical to task performance. If successful the results of this project will provide crucial data using converging methods on the role of PFC in top-down control. The proposed work has broad theoretical implications and will also inform translational physiologically based interventions for neurological and neurosurgical patients with PFC damage.